Affinage

SYNGAP1

Ras/Rap GTPase-activating protein SynGAP · UniProt Q96PV0

Length
1343 aa
Mass
148.3 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYNGAP1 encodes a brain-enriched Ras/Rap GTPase-activating protein concentrated at excitatory postsynaptic densities, where it acts as a master negative regulator of synaptic strength and a developmental brake on neuronal maturation (PMID:9581761, PMID:12427827, PMID:23141534). It is recruited to the PSD through direct binding of its C-terminal motif to the PDZ domains of PSD-95 and SAP102, residing in a macromolecular complex with the NMDA receptor (PMID:9581761, PMID:9620694). Catalytically, its GAP domain requires the adjacent C2 domain for full Rap inactivation, accelerating the Rap GTPase reaction ~10,000-fold via a switch II–assisting mechanism analogous to canonical RasGAPs (PMID:18323856). By inactivating Ras and Rap downstream of NMDA receptors, SynGAP suppresses ERK/MAPK signaling, AMPAR surface trafficking, and ERK-mTOR-Rheb-driven protein synthesis, thereby limiting excitatory transmission and gating NMDAR-dependent LTP (PMID:12427827, PMID:16537406, PMID:24391850). SynGAP activity is bidirectionally and combinatorially tuned by phosphorylation: CaMKII, CDK5, PLK2, and ROCK phosphorylate distinct sites that differentially shift the balance between Ras and Rap inactivation, and CaMKII phosphorylation drives rapid dispersal of SynGAP from the spine core during LTP to permit spine enlargement and AMPAR incorporation (PMID:14970204, PMID:25533468, PMID:30049443, PMID:25569349, PMID:35624196). SynGAP-α1 undergoes liquid-liquid phase separation with PSD-95 that targets it synaptically and is required for LTP, whereas isoforms lacking the PDZ-binding motif (β) instead promote dendritic arborization; this phase behavior is suppressed by O-GlcNAcylation at T1306 (PMID:32579114, PMID:35637289). Beyond catalysis, SynGAP exerts a structural role by competing with the AMPAR-TARP complex for incorporation into PSD condensates and by restricting access of other proteins to PSD-95 PDZ domains, and GAP-independent functions account for its control of seizure susceptibility (PMID:38422154, PMID:27623146, PMID:40294267). Developmentally, SynGAP represses premature dendritic spine maturation and circuit excitability during critical postnatal windows, controls cortical radial glia scaffolding and neurogenesis, and—antagonized by SRGAP2A—sets the tempo of human synaptic neoteny (PMID:23141534, PMID:37946050, PMID:39111306, PMID:39406239). SYNGAP1 haploinsufficiency causes intellectual disability with epilepsy through these combined synaptic and developmental defects, and patient-relevant expression can be restored by redirecting PTBP-dependent unproductive splicing (PMID:23141534, PMID:37149717, PMID:36917980).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Established SynGAP's identity as a synaptic Ras-GAP physically tethered to the PSD-95/NMDAR complex, defining its core molecular activity and localization.

    Evidence Reciprocal Co-IP, in vitro binding, GTPase assays, and subcellular fractionation in two independent studies

    PMID:9581761 PMID:9620694

    Open questions at the time
    • Did not resolve which downstream effectors of Ras are controlled in vivo
    • Rap as a substrate not yet addressed
  2. 2002 High

    Linked SynGAP genetically to NMDAR-dependent plasticity, showing it constrains basal ERK and is required for hippocampal LTP.

    Evidence Heterozygous KO mouse with LTP electrophysiology, ERK2 phospho-assay, and SynGAP/H-Ras epistasis

    PMID:12427827

    Open questions at the time
    • Did not separate developmental from acute contributions
    • Mechanism connecting ERK to AMPAR not defined
  3. 2004 High

    Defined how SynGAP activity is regulated and how it shapes spines, showing CaMKII phosphorylation tunes GAP activity and that both catalytic and PSD-95-binding functions are required for normal spine number.

    Evidence In vitro kinase/GAP assays with phosphosite mutagenesis, Ca2+-sensitive MUPP1/CaMKII complex Co-IP, and domain-rescue in KO neurons

    PMID:14970204 PMID:15312654 PMID:15470153

    Open questions at the time
    • Did not establish in vivo phosphosite stoichiometry
    • Relationship between Ras and Rap inactivation not yet dissected
  4. 2006 High

    Showed SynGAP bidirectionally controls AMPAR trafficking by differentially balancing ERK versus p38 MAPK signaling.

    Evidence Reciprocal overexpression/knockdown in neurons with mEPSC, surface biotinylation, and MAPK phospho-assays

    PMID:16537406

    Open questions at the time
    • Did not identify the molecular link between MAPK output and receptor insertion
  5. 2008 High

    Provided the structural-enzymatic basis for Rap inactivation and connected SynGAP to cytoskeletal regulation via Rac/cofilin.

    Evidence C2-GAP crystal structure with reconstituted GTPase assays; Ras/Rac-GTP pulldowns and phospho-cofilin assays in KO mice

    PMID:18323856 PMID:19074040

    Open questions at the time
    • Did not define which physiological signals select Ras vs Rap output
    • Rac regulation may be indirect
  6. 2011 Medium

    Demonstrated that activity drives SynGAP redistribution out of the PSD core while PSD-95 stays fixed, revealing dynamic synaptic relocation as a regulatory mechanism.

    Evidence Quantitative immunogold EM under basal, depolarization, and NMDA conditions

    PMID:21736925

    Open questions at the time
    • Single method, single lab
    • Did not establish the molecular trigger for redistribution
  7. 2012 High

    Revealed isoform diversity (α1/α2, alternative promoters) as a source of opposing effects on synaptic strength.

    Evidence Isoform overexpression with mEPSC, 5'-RACE, and primer extension in neurons

    PMID:22692543

    Open questions at the time
    • Did not establish endogenous isoform ratios in vivo
    • Mechanism of opposing effects unresolved
  8. 2013 Medium

    Identified SynGAP as a translational brake (ERK-mTOR-Rheb) and confirmed CaMKII-driven removal of both α isoforms from the PSD core upon NMDA stimulation.

    Evidence Knockdown/KO with 35S-methionine protein synthesis assay and pathway inhibitors; isoform-specific immunogold EM with CaMKII inhibitor

    PMID:23967245 PMID:24391850

    Open questions at the time
    • Protein synthesis link single lab
    • Did not quantify dispersal kinetics relative to plasticity
  9. 2014 High

    Quantified combinatorial phospho-control, showing CaMKII and CDK5 phosphorylate distinct sites that differentially shift the balance between Ras and Rap inactivation.

    Evidence In vitro kinase and GTPase assays with MS phosphosite mapping, mutagenesis, and NMDA-stimulated neurons

    PMID:25533468

    Open questions at the time
    • Did not establish in vivo phospho-occupancy during plasticity
    • Physiological consequence of Ras/Rap balance shift untested
  10. 2015 High

    Showed CaMKII-dependent SynGAP dispersal from spines transduces CaMKII activity into Ras-driven spine enlargement and AMPAR incorporation.

    Evidence Live imaging of tagged SynGAP during LTP with CaMKII inhibition and spine volume measurement

    PMID:25569349

    Open questions at the time
    • Did not resolve where dispersed SynGAP relocates functionally
  11. 2016 High

    Established a structural/scaffolding role: SynGAP-α1 restricts other proteins' access to PSD-95 PDZ domains, and revealed cell-autonomous requirement in GABAergic interneurons for inhibition and gamma oscillations.

    Evidence Affinity measurements, in vitro kinase (CaMKII, PLK2), PSD proteomics from Het mice; cell-type-specific conditional KO with EEG and behavior

    PMID:27623146 PMID:27827368

    Open questions at the time
    • Did not quantify in vivo competitive displacement dynamics
    • Interneuron and excitatory contributions to disease not weighed
  12. 2018 High

    Extended combinatorial phospho-regulation, showing PLK2 and CDK5 together additively boost HRas-GAP activity and uniquely activate Rap2-GAP activity.

    Evidence In vitro kinase and GTPase assays with MS phosphosite mapping

    PMID:30049443

    Open questions at the time
    • Single lab in vitro
    • Rap2 effect not validated in neurons
  13. 2019 Medium

    Identified non-canonical interactions and adulthood functionality, including a D1R complex controlling interneuron migration and reversal of deficits by adult SynGAP restoration.

    Evidence Co-IP, surface biotinylation, TAT-peptide migration assays; inducible adult gene restoration with video-EEG and memory tests

    PMID:31025938 PMID:31387938

    Open questions at the time
    • D1R interaction single lab
    • Adult-reversibility scope and durability not fully defined
  14. 2020 High

    Showed phase separation determines SynGAP function, with α1 LLPS targeting it synaptically for LTP while non-PDZ isoforms drive dendritic arborization.

    Evidence Isoform-specific KO/overexpression, LLPS reconstitution, LTP electrophysiology, dendritic morphology, and a phase-separation-disrupting mutant

    PMID:32579114

    Open questions at the time
    • Did not establish in vivo condensate dynamics during plasticity
  15. 2022 High

    Identified regulatory modifications of SynGAP condensate behavior: O-GlcNAcylation at T1306 suppresses LLPS, and ROCK phosphorylation at S842 promotes 14-3-3ζ binding, Ras-ERK activation, and PSD-95 dissociation.

    Evidence Protein semisynthesis with site-specific O-GlcNAc and LLPS assays; in vitro ROCK kinase reconstitution, Co-IP, and neuronal spine imaging

    PMID:35624196 PMID:35637289

    Open questions at the time
    • ROCK study single lab/HeLa reconstitution
    • In vivo relevance of T1306 O-GlcNAc cycling untested
  16. 2023 High

    Revealed SYNGAP1 control of human cortical neurogenesis and a tractable splicing mechanism for restoring expression in haploinsufficiency.

    Evidence Human cortical organoid and mouse haploinsufficiency imaging; CLIP-seq of PTBP1/2 on SYNGAP1 mRNA, splice assays, A3SS-deletion mouse rescue, and ASOs in patient iPSC-neurons

    PMID:36315645 PMID:36917980 PMID:37149717 PMID:37946050

    Open questions at the time
    • Organoid radial glia role single lab
    • Mnks-Syngap1 axis Medium confidence
    • Therapeutic durability of splice correction not established
  17. 2024 High

    Dissociated catalytic from structural functions, showing GAP activity is dispensable for LTP and behavior (mediated instead by condensate competition with the AMPAR-TARP complex) but required for intrinsic excitability, while the non-enzymatic role governs seizure susceptibility; also defined SYNGAP1's role in human synaptic neoteny via antagonism with SRGAP2A.

    Evidence GAP-dead knock-in mice with LTP, behavior, condensate competition biochemistry, PTZ seizure assays; xenotransplanted human neurons with combinatorial CRISPR loss-of-function and circuit recordings

    PMID:38422154 PMID:39111306 PMID:39406239 PMID:40294267

    Open questions at the time
    • Mechanism partitioning enzymatic vs structural roles across cell types incomplete
    • SRGAP2A antagonism epistasis single lab
    • How condensate competition encodes specific synaptic strength unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple kinase inputs, phase-separation state, and condensate competition are integrated in real time to set synaptic strength, and how enzymatic versus structural contributions are partitioned across distinct neuronal and developmental contexts, remains unresolved.
  • No unified quantitative model linking phospho-state, LLPS, and AMPAR competition
  • In vivo dynamics of condensate-based competition not directly imaged
  • Relative disease contribution of enzymatic vs structural deficits not parsed by cell type

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 2
Partners
CAMK2ACDK5DLG2DLG3DLG4DRD1PLK2YWHAZ
Complex memberships
MUPP1/CaMKII complexPSD-95/NMDA receptor postsynaptic complexSynGAP-PSD-95 phase-separated condensate

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SynGAP is a Ras-GTPase activating protein that interacts with the PDZ domains of PSD-95 and SAP102 in vitro and in vivo, is highly enriched at excitatory synapses, and is present in a large macromolecular complex with PSD-95 and the NMDA receptor; it stimulates GTPase activity of Ras, negatively regulating Ras activity at excitatory synapses. Co-immunoprecipitation, in vitro binding assays, GTPase activity assay, subcellular fractionation Neuron High 9581761
1998 p135 SynGAP is a major component of the postsynaptic density that binds to PSD-95 at synapses; its Ras-GTPase activating activity is inhibited by phosphorylation by CaMKII in the PSD protein complex, which would activate the MAP kinase pathway upon NMDA receptor activation. Biochemical purification, Co-immunoprecipitation, in vitro kinase/GAP activity assay, immunofluorescence localization Neuron High 9620694
2002 SynGAP regulates the ERK/MAPK signaling pathway downstream of NMDA receptors; heterozygous null SynGAP mutant mice show elevated basal ERK2 activation and strongly reduced LTP in hippocampal CA1, implicating SynGAP as a required component of NMDAR-dependent synaptic plasticity. Genetic knockout mouse model, electrophysiology (LTP measurement), biochemical ERK2 phosphorylation assay, double mutant epistasis (SynGAP/H-Ras) The Journal of neuroscience High 12427827
2004 Phosphorylation of SynGAP by CaMKII at serines 1123, 1058, 750/751/756, and 764/765 increases its Ras GTPase-activating activity by 70–95%; mutation of these sites reduces stimulation to 21%; phosphorylation at S765 and S1123 is increased in cortical neurons after NMDA treatment. In vitro kinase assay with recombinant protein, site-directed mutagenesis, phosphosite-specific antibodies, mass spectrometry, neuronal NMDA stimulation The Journal of biological chemistry High 14970204
2004 SynGAP forms a Ca2+-sensitive complex with MUPP1 and CaMKII via direct physical interaction with PDZ domains of MUPP1; Ca2+/CaM binding to CaMKII dissociates it from the complex, driving dephosphorylation of SynGAP, p38 MAPK inactivation, AMPA receptor potentiation, and increased AMPAR-containing clusters. Co-immunoprecipitation, peptide-induced complex disruption, siRNA knockdown, electrophysiology, immunofluorescence Neuron High 15312654
2004 SynGAP regulates spine formation: neurons from SynGAP knockout mice show accelerated spine and synapse formation with larger spines; rescue requires both the GAP domain and the C-terminal PSD-95-binding domain, demonstrating that both GAP catalytic activity and PSD-95 association are necessary for normal spine regulation. Genetic knockout mouse neurons in culture, rescue with wild-type vs. mutant SynGAP constructs (GAP domain mutant and PDZ-binding deletion mutant), electrophysiology (mEPSC), immunocytochemistry The Journal of neuroscience High 15470153
2006 SynGAP overexpression in hippocampal neurons depresses AMPAR-mediated mEPSCs and reduces synaptic AMPAR surface expression and plasma membrane insertion; SynGAP knockout or siRNA knockdown increases synaptic transmission; overexpression decreases ERK activation while increasing p38 MAPK signaling; knockout shows the reverse, indicating SynGAP regulates AMPAR trafficking via differential MAPK pathway control. Overexpression and knockout/siRNA knockdown in cultured neurons, whole-cell patch-clamp (mEPSC), surface biotinylation, MAPK phosphorylation assays Proceedings of the National Academy of Sciences High 16537406
2008 The C2 domain of SynGAP is essential for RapGAP activity: the isolated GAP domain has no detectable RapGAP activity, but the C2-GAP fragment stimulates Rap GTPase reaction ~10,000-fold; crystal structure of C2-GAP reveals a mechanism where C2 domain moves toward switch II of Rap to assist catalysis, analogous to canonical RasGAPs. In vitro GTPase activity assay, X-ray crystallography, biochemical mutagenesis, modeling EMBO reports High 18323856
2008 SynGAP is a key regulator of spine morphology in adult mice: heterozygous deletion elevates both Ras-GTP and Rac-GTP levels in forebrain, increases steady-state phospho-cofilin (downstream of Rac), and disrupts NMDA-induced transient cofilin dephosphorylation in neurons; SynGAP mediates a rate-limiting step in NMDAR-dependent cytoskeletal regulation. Heterozygous knockout mouse, RhoGEF pull-down for Ras/Rac-GTP, phospho-cofilin immunoblot, pharmacological NMDA treatment, electrophysiology (EPSP depression) The Journal of neuroscience High 19074040
2011 SynGAP moves out of the PSD core upon depolarization or NMDA application: immunogold EM shows significant decrease of SynGAP at the PSD core (0–40 nm from membrane) and concomitant increase at 40–120 nm zone; PSD-95 does not redistribute under the same conditions; redistribution is reversible. Immunogold electron microscopy of rat hippocampal neuronal cultures under basal, K+-depolarization, and NMDA conditions Neuroscience Medium 21736925
2012 SynGAP isoforms α1 and α2 exert opposing effects on synaptic strength: overexpression of α1 C-terminus decreases mEPSC amplitude/frequency while α2 C-terminus increases them; N-terminal peptide sequences from alternative promoters modulate the magnitude of this effect; N-terminal diversity arises from activity-regulated alternative promoter usage. Overexpression of isoform constructs in hippocampal neurons, whole-cell patch-clamp (mEPSC), 5'-RACE, primer extension Nature communications High 22692543
2012 Pathogenic SYNGAP1 mutations cause premature dendritic spine synapse maturation during early postnatal development, dramatically enhancing hippocampal excitability and producing behavioral abnormalities; inducing mutations after critical developmental windows has minimal impact, and repairing mutations in adulthood does not improve behavior/cognition, establishing SynGAP as a developmental repressor of neural excitability. Conditional and inducible Syngap1 mouse mutants, spine morphology analysis, electrophysiology, behavioral testing, temporal genetic rescue Cell High 23141534
2013 SynGAP limits excitatory synaptic strength partly by suppressing protein synthesis in cortical neurons through an ERK-mTOR-Rheb pathway; GluN2B-containing NMDARs and CaMKII act upstream of SynGAP in a signaling cascade required for translation-dependent homeostatic synaptic plasticity. SynGAP knockdown/knockout in cultured cortical neurons, pharmacological manipulation, 35S-methionine incorporation (protein synthesis assay), pathway inhibitor experiments PloS one Medium 24391850
2013 CaMKII activation promotes removal of both SynGAP-α1 and SynGAP-α2 from the PSD core upon NMDA stimulation; tatCN21 (CaMKII inhibitor) blocks NMDA-induced redistribution of both isoforms; both isoforms can be phosphorylated by endogenous CaMKII in isolated PSDs. Immunogold electron microscopy with isoform-specific antibodies, CaMKII inhibitor peptide application, in situ PSD phosphorylation assay PloS one Medium 23967245
2014 Phosphorylation of SynGAP by CaMKII increases HRas GAP activity by 25% and Rap1 GAP activity by 76%; phosphorylation by CDK5 increases HRas GAP activity by 98% and Rap1 GAP activity by 20%; CDK5 phosphorylates SynGAP primarily at Ser-773 and Ser-802 with opposing individual effects; dual CaMKII+CDK5 phosphorylation produces additive HRas effects; phosphorylation differentially shifts the balance between Ras and Rap inactivation. In vitro kinase assay with recombinant purified SynGAP, GTPase activity assay, mass spectrometry phosphosite mapping, site-directed mutagenesis, NMDA-stimulated neurons The Journal of biological chemistry High 25533468
2015 SynGAP is rapidly dispersed from dendritic spines upon LTP induction in hippocampal neurons; this dispersion depends on CaMKII phosphorylation of SynGAP; the degree of acute SynGAP dispersion predicts maintenance of spine enlargement; CaMKII-driven SynGAP dispersal transduces CaMKII activity to Ras-mediated spine enlargement and AMPAR synaptic incorporation. Live-cell imaging of fluorescently tagged SynGAP in hippocampal neurons, LTP induction, CaMKII inhibition, spine volume measurement Neuron High 25569349
2016 SynGAP-α1 regulates PSD composition by restricting binding of other proteins to PDZ domains of PSD-95; phosphorylation by CaMKII and PLK2 decreases SynGAP-α1 affinity for PDZ domains, freeing sites for other proteins; three critical postsynaptic signaling proteins binding PSD-95 PDZ domains are present at higher concentration in PSDs from Syngap1 heterozygous mice. Biochemical affinity measurements, in vitro kinase assays, PSD fractionation from heterozygous mice, quantitative proteomics/immunoblot eLife High 27623146
2016 Syngap1 haploinsufficiency in GABAergic cells (medial ganglionic eminence-derived) cell-autonomously impairs perisomatic innervation by parvalbumin-positive basket cells, reduces inhibitory synaptic activity, decreases cortical gamma oscillation power, and causes cognitive deficits. Cell-type-specific Syngap1 conditional knockout, immunofluorescence, patch-clamp electrophysiology, in vivo EEG, behavioral testing Nature communications High 27827368
2018 Phosphorylation of SynGAP by PLK2 stimulates HRas GAP activity by 65% and Rap1 GAP activity by 16%; combined PLK2+CDK5 phosphorylation produces additive HRas increase (~230%) and also activates Rap2 GAP activity (~40–50%), an effect not produced by either kinase alone; Ca2+/CaM increases the rate and stoichiometry of PLK2 phosphorylation of SynGAP. In vitro kinase assay with recombinant purified SynGAP, GTPase activity assay, mass spectrometry Biochemical and biophysical research communications High 30049443
2019 SynGAP interacts with the dopamine D1 receptor (D1R) in prenatal mouse brain; this interaction facilitates D1R plasma membrane localization and promotes D1R-mediated PKA and p38 MAPK phosphorylation; disrupting this complex with a TAT peptide impairs tangential migration of GABAergic interneurons and alters actin and microtubule dynamics. Co-immunoprecipitation from prenatal brain tissue, cell surface biotinylation, phosphorylation assays, TAT-peptide disruption, interneuron migration assay in vivo Science signaling Medium 31387938
2020 SynGAP-α1, which undergoes liquid-liquid phase separation (LLPS) with PSD-95, is highly enriched in synapses and required for LTP; SynGAP-β, which lacks PSD-95 PDZ-binding, is less synaptically targeted and promotes dendritic arborization; a SynGAP-α1 mutation disrupting phase separation abolishes LTP regulation and redirects its function to dendritic development. Isoform-specific overexpression and knockout in mouse neurons, LLPS assay, live imaging, electrophysiology (LTP), dendritic morphology analysis, subcellular fractionation eLife High 32579114
2022 O-GlcNAcylation of SynGAP at T1306 acts as a suppressor of SynGAP/PSD-95 liquid-liquid phase separation; O-GlcNAcylation blocks SynGAP interaction with PSD-95 in a dominant-negative manner; O-GlcNAc cycling is reversibly regulated by OGT and OGA. Protein semisynthesis for site-specific O-GlcNAcylation, in vitro and cell-based LLPS assays, endogenous O-GlcNAc site mapping from rat brain by MS, OGT/OGA pharmacological manipulation Nature chemistry High 35637289
2022 Rho-kinase (ROCK) phosphorylates SynGAP1 at Ser842, increasing its interaction with 14-3-3ζ, which activates Ras-ERK signaling and promotes SynGAP1 dissociation from PSD-95; NMDA receptor stimulation (glycine-LTP protocol) activates this pathway to induce spine enlargement in striatal neurons, and ROCK inhibition prevents these effects. In vitro kinase assay (reconstitution in HeLa cells), co-immunoprecipitation, phospho-specific immunoblot, ROCK inhibitor treatment, live imaging of spine morphology in neurons Neurochemical research Medium 35624196
2023 SYNGAP1 is expressed in apical domains of human radial glia cells (hRGCs); SYNGAP1 haploinsufficiency in human cortical organoids dysregulates cytoskeletal dynamics, impairs hRGC scaffolding and division plane orientation, resulting in disrupted cortical lamination and accelerated maturation of projection neurons; confirmed in mouse Syngap1 haploinsufficiency model with imbalanced progenitor-to-neuron ratios. Human cortical organoid model with SYNGAP1 haploinsufficiency, immunofluorescence, live imaging of hRGCs, mouse model validation Nature neuroscience Medium 37946050
2024 SynGAP regulates synaptic plasticity and cognition independently of its GAP enzymatic activity: inactivating mutations in the GAP domain do not inhibit LTP or cause behavioral deficits in mice; instead, SynGAP modulates synaptic strength by physically competing with the AMPA receptor-TARP complex for incorporation into molecular condensates with synaptic scaffold proteins. GAP-domain inactivating knock-in mouse models, electrophysiology (LTP), behavioral testing, molecular condensate assays, biochemical competition assays Science High 38422154
2024 Intrinsic excitability deficits (reduced input resistance, increased rheobase) in cortical excitatory neurons from heterozygous Syngap1 KO mice are recapitulated in GAP-deficient Syngap1 mutants, implicating GAP enzymatic activity; however, seizure severity and PTZ-induced seizure susceptibility are elevated in KO but unaffected in GAP-deficient mutants, implicating the structural (non-enzymatic) role of SynGAP in seizure regulation. Heterozygous KO and GAP-dead knock-in mouse models, whole-cell patch-clamp (intrinsic excitability), PTZ-induced seizure threshold assay, video-EEG Proceedings of the National Academy of Sciences High 40294267
2001 SynGAP-β isoform lacks the C-terminal PSD-95-binding motif yet is enriched in PSD fractions; SynGAP-β does not interact with PSD-95 but specifically interacts with non-phosphorylated α-subunit of CaMKII through its unique C-terminal tail; at least five distinct SynGAP protein isoforms exist with different C-termini. cDNA cloning, subcellular fractionation, Co-immunoprecipitation, in vitro binding assay The Journal of biological chemistry Medium 11278737
2001 After cerebral ischemia, SynGAP undergoes increased tyrosine phosphorylation, which enables it to bind the SH2 domains of Src and Fyn in a phosphorylation-dependent manner; this is accompanied by decreased co-immunoprecipitation of SynGAP with PSD-95. Four-vessel occlusion ischemia model, anti-phosphotyrosine immunoblot, GST-SH2 pulldown, co-immunoprecipitation Journal of cerebral blood flow and metabolism Medium 11487731
2020 PSD-93 directly interacts with SynGAP and mediates SynGAP ubiquitination and proteasomal degradation following ischemic brain injury; the 670-685 amino acid sequence of SynGAP is essential for binding PSD-93; NMDA receptor activation promotes PSD-93-dependent SynGAP degradation. Co-immunoprecipitation, MG-132 proteasome inhibitor, PSD-93 knockout mice, ubiquitination assay, TAT-peptide competition, cerebral ischemia-reperfusion model Translational stroke research Medium 32130656
2023 PTBP1/2 directly bind SYNGAP1 mRNA and promote alternative splicing leading to nonsense-mediated mRNA decay (A3SS-NMD); antisense oligonucleotides disrupting PTBP2 binding redirect splicing and increase SYNGAP1 mRNA and protein expression; PTBP2-targeting ASOs partially restore SYNGAP1 expression in patient-derived haploinsufficient iPSC-neurons. CLIP-seq (PTBP2 footprinting), splice assays, ASO treatment, qRT-PCR, immunoblot in iPSC-neurons from patients Nature communications High 37149717
2023 PTBP1/2 directly promote SYNGAP1 alternative 3' splice site (A3SS) inclusion leading to nonsense-mediated decay; genetic deletion of the Syngap1 A3SS in mice upregulates Syngap1 protein and rescues LTP and membrane excitability deficits in heterozygous Syngap1 KO mice; a splice-switching oligonucleotide converts SYNGAP1 unproductive isoform to functional form in human iPSC-derived neurons. Genetic A3SS deletion mouse model, electrophysiology (LTP, membrane excitability), splice-switching oligonucleotide in human iPSC-neurons, PTBP binding assays Neuron High 36917980
2023 Mnk1 immunoprecipitates with Syngap1 and phosphorylates it at S788; Syngap1 S788 phosphorylation is reduced in Mnk1/2 double knockout mice; Syngap1 knockdown reverses memory deficits in Mnk1/2 KO mice; pharmacological Mnk inhibition rescues autism-related phenotypes in Syngap1+/- mice, establishing a Mnks-Syngap1 axis regulating memory and autism-related behavior. Co-immunoprecipitation, phospho-S788 immunoblot in Mnk KO mice, Syngap1 knockdown epistasis, behavioral testing, pharmacological Mnk inhibition in Syngap1+/- mice Brain Medium 36315645
2024 SYNGAP1 haploinsufficiency in human neurons xenotransplanted into mouse cortex causes strong acceleration of morphological and functional synaptic formation and maturation, disrupted synaptic plasticity, and precocious acquisition of responsiveness to visual stimulation; the effect is cell-autonomous, establishing a SYNGAP1-dependent requirement for human neuronal synaptic neoteny. Xenotransplantation of CRISPR-edited SYNGAP1-haploinsufficient human cortical neurons into mouse cortex, live imaging, electrophysiology, in vivo visual response recording Neuron High 39111306
2024 SRGAP2A postsynaptically antagonizes SYNGAP1 to control the tempo of synaptogenesis; SRGAP2B/C (human-specific duplications) promote neoteny by reducing synaptic SRGAP2A, thereby increasing postsynaptic SYNGAP1; combinatorial loss-of-function of SRGAP2A and SYNGAP1 in vivo reveals their reciprocal antagonism sets the speed of human synaptogenesis. Xenotransplantation of human cortical neurons with combinatorial CRISPR loss-of-function, in vivo imaging, synaptic marker quantification Neuron Medium 39406239
2005 Conditional homozygous deletion of SynGAP leads to cell-autonomous neuronal apoptosis (caspase-3 activation) in hippocampus and cortex; apoptosis correlates inversely with SynGAP protein level, indicating SynGAP plays a role in regulating the onset of apoptotic neuronal death. Conditional cre/loxP knockout mouse, caspase-3 immunohistochemistry, Western blot quantification of SynGAP protein levels The European journal of neuroscience Medium 15733080
2019 Adult restoration of SynGAP protein in a mouse model of SYNGAP1 haploinsufficiency improved behavioral and electrophysiological measures of memory and eliminated interictal events that worsened during sleep, demonstrating that SynGAP retains therapeutically relevant biological functions in adulthood. Inducible gene restoration in adult heterozygous mice, 24-hour video-EEG, behavioral memory tests eLife Medium 31025938

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 542 9581761
1998 A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 500 9620694
2012 Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 298 23141534
2002 SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 279 12427827
2009 Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. The New England journal of medicine 271 19196676
2004 SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron 238 15312654
2015 Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron 226 25569349
2012 Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Human mutation 212 23161826
2006 SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proceedings of the National Academy of Sciences of the United States of America 208 16537406
2018 SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology 162 30541864
2004 SynGAP regulates spine formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 160 15470153
2016 Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Journal of medical genetics 145 26989088
2011 De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biological psychiatry 145 21237447
2020 Twenty Years of SynGAP Research: From Synapses to Cognition. The Journal of neuroscience : the official journal of the Society for Neuroscience 122 32075947
2008 SynGAP regulates steady-state and activity-dependent phosphorylation of cofilin. The Journal of neuroscience : the official journal of the Society for Neuroscience 103 19074040
2004 Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. The Journal of biological chemistry 103 14970204
2009 Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 99 19145222
2016 SYNGAP1: Mind the Gap. Frontiers in cellular neuroscience 97 26912996
2014 Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly. Biological psychiatry 96 25444158
2015 De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. American journal of medical genetics. Part A 87 26079862
2008 The C2 domain of SynGAP is essential for stimulation of the Rap GTPase reaction. EMBO reports 87 18323856
2020 SynGAP isoforms differentially regulate synaptic plasticity and dendritic development. eLife 80 32579114
2018 Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders. Molecular and cellular neurosciences 75 29580901
2016 A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density. eLife 73 27623146
2012 SynGAP isoforms exert opposing effects on synaptic strength. Nature communications 73 22692543
2016 Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function. Nature communications 71 27827368
2019 Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior. eLife 70 31025938
2019 Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice. Neuropsychopharmacology reports 69 31323176
2015 Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 67 26558778
2017 3'UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function. Cell reports 66 28954225
2015 Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis. Human molecular genetics 66 25882707
2013 SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PloS one 66 24391850
2014 Phosphorylation of synaptic GTPase-activating protein (synGAP) by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclin-dependent kinase 5 (CDK5) alters the ratio of its GAP activity toward Ras and Rap GTPases. The Journal of biological chemistry 65 25533468
2010 Disruption of hippocampus-regulated behavioural and cognitive processes by heterozygous constitutive deletion of SynGAP. The European journal of neuroscience 63 20105235
2024 SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity. Science (New York, N.Y.) 61 38422154
2023 Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis. Nature neuroscience 61 37946050
2022 O-GlcNAcylation modulates liquid-liquid phase separation of SynGAP/PSD-95. Nature chemistry 61 35637289
2020 SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 32887745
2019 SYNGAP1 mutations: Clinical, genetic, and pathophysiological features. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 55 31454529
2023 Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing. Neuron 54 36917980
2019 Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression. Journal of neurodevelopmental disorders 54 31395010
2001 Characterization of a novel synGAP isoform, synGAP-beta. The Journal of biological chemistry 52 11278737
2020 Low-Dose Perampanel Rescues Cortical Gamma Dysregulation Associated With Parvalbumin Interneuron GluA2 Upregulation in Epileptic Syngap1+/- Mice. Biological psychiatry 44 32107006
2005 Differential expression of two NMDA receptor interacting proteins, PSD-95 and SynGAP during mouse development. The European journal of neuroscience 44 15673435
2020 SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain. Journal of neurochemistry 40 32068252
2018 The first international conference on SYNGAP1-related brain disorders: a stakeholder meeting of families, researchers, clinicians, and regulators. Journal of neurodevelopmental disorders 40 29402231
2011 SynGAP moves out of the core of the postsynaptic density upon depolarization. Neuroscience 40 21736925
2005 A role for synGAP in regulating neuronal apoptosis. The European journal of neuroscience 40 15733080
2018 Chewing induced reflex seizures ("eating epilepsy") and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases. Seizure 32 30685520
2013 Camkii-mediated phosphorylation regulates distributions of Syngap-α1 and -α2 at the postsynaptic density. PloS one 31 23967245
2011 A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia 29 22050443
2023 Mapping PTBP2 binding in human brain identifies SYNGAP1 as a target for therapeutic splice switching. Nature communications 28 37149717
2020 PSD-93 Interacts with SynGAP and Promotes SynGAP Ubiquitination and Ischemic Brain Injury in Mice. Translational stroke research 26 32130656
2013 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. American journal of medical genetics. Part A 26 23687080
2004 Impaired SynGAP expression and long-term spatial learning and memory in hippocampal CA1 area from rats previously exposed to perinatal hypoxia-induced insults: beneficial effects of A68930. Neuroscience letters 26 15500970
2022 Clinical and behavioural features of SYNGAP1-related intellectual disability: a parent and caregiver description. Journal of neurodevelopmental disorders 24 35655128
2017 Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report. BMC medical genetics 24 28576131
2020 Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2. Genes, brain, and behavior 22 33347690
2012 Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout. Learning & memory (Cold Spring Harbor, N.Y.) 22 22700469
2024 Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism. Epilepsia 21 38470175
2017 Anchoring high concentrations of SynGAP at postsynaptic densities via liquid-liquid phase separation. Small GTPases 21 28524815
2015 SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG. Neuropediatrics 21 26110312
2022 Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency. Brain : a journal of neurology 19 34791091
2022 Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection. eLife 19 35394425
2021 Phenotypes in Children With SYNGAP1 Encephalopathy in China. Frontiers in neuroscience 19 34924933
2018 Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in Syngap1+/- mice. Pharmacological reports : PR 19 29940508
2001 Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 19 11487731
2020 Pressure Sensitivity of SynGAP/PSD-95 Condensates as a Model for Postsynaptic Densities and Its Biophysical and Neurological Ramifications. Chemistry (Weinheim an der Bergstrasse, Germany) 18 31910298
2019 Disruption of SynGAP-dopamine D1 receptor complexes alters actin and microtubule dynamics and impairs GABAergic interneuron migration. Science signaling 17 31387938
2024 SYNGAP1 deficiency disrupts synaptic neoteny in xenotransplanted human cortical neurons in vivo. Neuron 16 39111306
2023 Mouse models of SYNGAP1-related intellectual disability. Proceedings of the National Academy of Sciences of the United States of America 16 37669379
2020 Multi-parametric analysis of 57 SYNGAP1 variants reveal impacts on GTPase signaling, localization, and protein stability. American journal of human genetics 16 33308442
2019 Differential Regulation of Syngap1 Translation by FMRP Modulates eEF2 Mediated Response on NMDAR Activity. Frontiers in molecular neuroscience 16 31143100
2019 Tumor Suppression of Ras GTPase-Activating Protein RASA5 through Antagonizing Ras Signaling Perturbation in Carcinomas. iScience 16 31654850
2024 Accelerating therapeutic development and clinical trial readiness for STXBP1 and SYNGAP1 disorders. Current problems in pediatric and adolescent health care 14 38472035
2024 Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition. Neuron 14 39406239
2021 Syngap1 regulates experience-dependent cortical ensemble plasticity by promoting in vivo excitatory synapse strengthening. Proceedings of the National Academy of Sciences of the United States of America 14 34404727
2021 Experiential modulation of social dominance in a SYNGAP1 rat model of Autism Spectrum Disorders. The European journal of neuroscience 14 34672048
2020 A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency. eLife 14 31939740
2009 Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice. Behavioral neuroscience 14 19824778
2024 Key roles of C2/GAP domains in SYNGAP1-related pathophysiology. Cell reports 13 39269903
2023 Mnk1/2 kinases regulate memory and autism-related behaviours via Syngap1. Brain : a journal of neurology 13 36315645
2018 Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases. Biochemical and biophysical research communications 13 30049443
2003 Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats. Neuroscience letters 13 12951199
2025 Dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility. Proceedings of the National Academy of Sciences of the United States of America 12 40294267
2024 Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability. Translational psychiatry 12 39358332
2022 Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model. Brain communications 12 36349120
2015 Wnt-related SynGAP1 is a neuroprotective factor of glutamatergic synapses against Aβ oligomers. Frontiers in cellular neuroscience 12 26124704
2024 Haploinsufficiency of Syngap1 in Striatal Indirect Pathway Neurons Alters Motor and Goal-Directed Behaviors in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 10 39358043
2022 Effects of Cosolvents and Crowding Agents on the Stability and Phase Transition Kinetics of the SynGAP/PSD-95 Condensate Model of Postsynaptic Densities. The journal of physical chemistry. B 10 35171623
2022 Rho-Rho-Kinase Regulates Ras-ERK Signaling Through SynGAP1 for Dendritic Spine Morphology. Neurochemical research 10 35624196
2021 Pharmacological intervention in young adolescents rescues synaptic physiology and behavioural deficits in Syngap1+/- mice. Experimental brain research 10 34739555
2011 Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization. Journal of neurophysiology 10 21525372
2008 Differential distribution of synGAP alpha1 and synGAP beta isoforms in rat neurons. Brain research 10 18824155
2024 SynGAP: a synteny-based toolkit for gene structure annotation polishing. Genome biology 9 39138517
2023 Case report: Off-label use of low-dose perampanel in a 25-month-old girl with a pathogenic SYNGAP1 variant. Frontiers in neurology 9 37662032
2022 Phenotype and genotype analyses of Chinese patients with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations. Frontiers in genetics 9 36583017
2018 Clinical Transcriptome Sequencing Confirms Activation of a Cryptic Splice Site in Suspected SYNGAP1-Related Disorder. Molecular syndromology 9 30800045
2017 Pharmacoresistant epileptic eyelid twitching in a child with a mutation in SYNGAP1. Epileptic disorders : international epilepsy journal with videotape 9 28721930
2004 PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus. Brain research 9 15044063

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